Compositions and method for treatment and prophylaxis of inflammatory bowel disease

ABSTRACT

Methods and compositions for treating inflammatory bowel disease involve the use of targeted antibiotics in combination with probiotic formulations. The probiotics mitigate many of the deleterious side effects associated with antibiotic use and permit the antibiotic to be administered at a higher dose and for a longer duration than would otherwise be possible in the absence of the probiotic. The practice of the invention may reduce or eliminate the use of immunosuppressants in the treatment and management of IBD.

FIELD OF INVENTION

The present invention relates generally to compositions and methods forthe prophylaxis and treatment of inflammatory bowel disease (IBD) due tobacterial infection. More specifically, this invention envisions the useof probiotic formulations in combination with antibiotics to treat IBDsymptoms and to reduce the risk of relapse.

BACKGROUND

Inflammatory bowel disease (IBD) is a group of inflammatory conditionsof the colon and small intestine that affect over two million people inthe United States and an estimated eight million people worldwide. Thetwo phenotypes of IBD most commonly referred to are Crohn's disease (CD)and ulcerative colitis (UC). CD commonly manifests as inflammation ofthe small intestine, but can affect other parts of the body as well. UCis usually characterized by inflammation of the mucosa of the colon andrectum. Symptoms of IBD most commonly include fever, vomiting, diarrhea,bloody stool (hematochezia), abdominal pain, and weight loss, but alsomay include a host of other problems. The severity of symptoms mayimpair the quality of life of patients that suffer from IBD.

Although the etiology of IBD is poorly understood, many theories havebeen proposed. UC and CD are commonly regarded as autoimmune diseases,with evidence suggesting they are the result of a misdirected immuneresponse. The etiology of IBD appears to involve complex interactions ofgenetic predisposition, environmental factors, disruption of theintestinal microbiome, and an overly aggressive immune response. Inaddition, evidence linking the ability of intestinal epithelial cells tomodify the mucosal immune response, may suggest an invasive bacterialpathway. The integrity of the gut epithelial barrier is critical ininfluencing progression to disease. Imbalance in intestinal microbiotaof gut friendly bacteria destroyed by antibiotics as well asopportunistic pathogens are implicating factors as well. Additionalfactors influencing activation may include the unfolded protein response(a result of cellular stress), toll like receptors, invasive bacteria,TNF factors, DNA/RNA genetic mutations effecting encoding proteinsIL-10R1-IL10R2, spontaneous mutation of normal gut bacteria,uncontrolled T-cell activation, and enteroinvasive and adherent invasivestrains of E. coli bacteria. Disruption in the gut epithelial barrierwhen bacterial overgrowth overwhelms the body's defense mechanism tocope, the immune/inflammatory response, if left unchecked, often resultsin chronic inflammation, a precursor to full blown disease. Theinvolvement of luminal bacteria as a cause of chronic inflammation anddisease is well documented. See, e.g., Kucharzik et al., “Recentunderstanding of IBD pathogenesis: implications for future therapies,”Inflamm. Bowel Dis., 2006 November; 12(11):1068-83. Genetic studies haveimplicated IL12B and NOD2 in increased susceptibility to Mycobacterialdisease, and suggest that this combination of genetics and bacterialinfection are implicating factors in Cronh's disease as well asulcerative colitis. The possibility therefore exists as to Mycobacteriuminfection being among the several microbial triggers in IBD.

Patients with IBD have been reported to house an abnormal microbiota.Whether this altered flora is the cause or the result of chronicinflammation remains unclear. As yet, questions remain whether commensalenteric bacteria or invasive strains of pathogenic bacteria,particularly Escherichia coli, are a direct trigger cause in IBD. Bothmay be contributing factors in different subsets of patients.

Involvement of intestinal microflora in the pathogenesis of IBD has beensuggested but trials on the use of antibiotic treatment in patients withUC have produced contrasting results. See, for example, M. Guslandi,“Antibiotics for inflammatory bowel disease: do they work?” Eur. J.Gastroenterol. Hepatol., 2005 February; 17(2):145-7; Gionchetti et al.,“Review—antibiotic treatment in inflammatory bowel disease: rifaximin, anew possible approach,” Eur. Rev. Med. Pharmacol. Sci., 1999January-February; 3(1):27-30. However, the weight of evidence supportsthe use of antibiotics such as metronidazole, ciprofloxacin, orrifaximin in the treatment of IBD. See, Rubin, D. T., et al., “Role ofantibiotics in the management of inflammatory bowel disease: a review,”Rev. Gastroenterol. Disord., 2005; 5 Suppl. 3:S10-5. Studies by J. T.Danzi and others demonstrate the effectiveness of adjuvant use ofsulfamethoxazole-trimethoprin in patients with CD and UC in terms ofsteroid withdrawal and maintenance of remission. See Danzi, J. T.“Trimethoprim-Sulfamethoxazole Therapy of Inflammatory Bowel Disease,”Gastroentemology, Vol. 96, No. 5, Part 2, p. A1110. However, the use ofsulfamethoxazole-trimethoprin as a first-line therapy, rather than as anadjuvant to immunosuppressant therapy, is not suggested.

One complication associated with the use of broad-spectrum antibioticsis the depletion of beneficial microflora in the gut, leading toopportunistic infection by competing bacteria in the intestine,including Clostridium difficile. C. difficile infection can limit theduration of antibiotic therapy and can lead to pseudomembranous colitis,which may compound the symptoms of IBD. See Trnka, Y. M., et al.,“Association of Clostridium difficile toxin with symptomatic relapse ofchronic inflammatory bowel disease,” Gastroenterology, 1981 April;80(4):693-6; Freeman, H. J., “Recent developments on the role ofClostridium difficile in inflammatory bowel disease,” World J.Gastroenterol., 2008 May 14; 14(18):2794-6. In fact, it has beensuggested that the frequent use of broad spectrum antibiotics intreating IBD could exacerbate symptoms and prevent remission of UCsymptoms. See Miner, J. et al., “Steroid-refractory ulcerative colitistreated with corticosteroids, metronidazole and vancomycin: a casereport,” BMC Gastroenterol., 2005; 5:3. Many antibiotics currently usedhave been ineffective in achieving sustained control of remission inpart due to dosage and duration.

Probiotics are live microbial organisms that beneficially affect themicrobiome of the host and treatment of various disorders of thegastrointestinal tract, including IBD, using probiotics is well-known.See, e.g., Schultz M., et al, “Rationale for probiotic treatmentstrategies in inflammatory bowel disease,” Expert Rev. Gastroenterol.Hepatol., 2008 June; 2(3):337-55. For example, treatment of IBD usingspecific probiotic E. coli strains is disclosed in U.S. Pat. No.7,018,629, to Jacob et al. Likewise, prophylaxis and treatment of IBDwith an endogenous strain of Bifidobacterium is described in U.S. PatentPub. No. 2002/0006432, to Collins et al. However, probiotics alone willnot cure IBD, nor will they be a direct cause of remission.

The combination of probiotics and antibiotics has been proposed. Forexample, U.S. Pat. No. 6,461,607 to S. Farmer describes therapeuticcompositions for the treatment of a gastrointestinal infection caused bypathogenic bacteria, comprising antibiotic-resistant lactic-acidproducing bacteria and an antibiotic, although no mention is made of thetreatment of IBD.

There clearly is a continuing need for new therapies in the treatmentand control of IBD. It is therefore an object of this invention toprovide compositions and methods for an alternative treatment option forIBD.

SUMMARY OF INVENTION

The invention is premised on the theory that IBD may result from anoveractive immune response to invasive or commensal pathogenic bacterialinfection in the gastrointestinal tract. Therefore, in IBD cases wherepathogenic bacterial infection is suspected, it may be possible toachieve clinical remission of symptoms and prevent relapse withhigh-dose antibiotics administered for a duration of time sufficient tocompletely eradicate the bacterial antigen and its spores, allowing forrestoration of the gut epithelial barrier. The invention also envisionsthe use of high-dose, selective probiotics to counter the deleteriouseffects of antibiotic therapy on the natural enteric microflora andpromote healing of the mucosa and intestinal epithelial barrier byrestoring and maintaining the natural enteric microflora.

In one aspect of the invention, therapeutic compositions are providedcomprising antibiotics and probiotics. The antibiotics and probioticsmay be combined in a unitary dosage form to improve patient compliancewith the treatment protocols. Accordingly, one aspect of the inventionrelates to a multi-layer tablet for the treatment or prophylaxis ofinflammatory bowel disease due to pathogenic bacterial infection. Themulti-layer tablets comprises:

(i) a delayed-release layer comprising an amount of antibiotic effectiveto reduce colonization of pathogenic bacteria in the gastrointestinaltract, preferably a combination of:

sulfamethoxazole, and

trimethoprim; and

(ii) an immediate-release layer comprising a probiotic formulation in anamount effective to restore normal microflora colonies in the gut,preferably including at least one strain selected from:

Bifidobacterium bifidum;

Bifidobacterium breve;

Bifidobacterium infantis;

Bifidobacterium longum;

Lactobacillus acidophilus;

Lactobacillus bulgaricus;

Lactobacillus paracasein;

Saccharomyces boulardii, and combinations thereof.

The immediate-release layer preferably surrounds the delayed-releaselayer and releases the probiotic formulation upon contact with gastricfluid in the stomach. The delayed-release layer preferably comprises anenteric coating of a polymer which releases the antibiotic primarily inthe terminal ileum.

In another aspect of the invention, a method for treatment orprophylaxis of inflammatory bowel disease due to bacterial infection isprovided. The method is based on the principle that achieving andmaintaining remission requires high doses of targeted antibiotics and aduration of treatment sufficient to completely eradicate the offendingbacterial antigens and their components. Therefore, the method of theinvention may comprise daily administration for extended durations,preferably for a period of at least 120 days, of a compositioncomprising:

(i) an amount of antibiotic effective to reduce colonization ofpathogenic bacteria in the gastrointestinal tract, the antibioticpreferably comprising a combination of sulfamethoxazole andtrimethoprim, and

(ii) a probiotic formulation in an amount effective to restore normalmicroflora colonies in the gut, the probiotic formulation preferablyincluding at least one strain selected from those listed above.

The daily dosage of both antibiotic and probiotic will typically behigher during the treatment of active symptoms than during themaintenance or prophylaxis stage of therapy. For example, a preferredtherapeutic regimen comprises, in sequential steps:

(a) a first step for the treatment of active symptoms comprising twicedaily administration of about 800 mg of sulfamethoxazole, about 160 mgof trimethoprim, and at least about 20 billion cells of probiotics (fora total daily dose of about 1,600 mg of sulfamethoxazole, about 320 mgof trimethoprim, and at least about 40 billion cells of probiotics), fora period from 120 to 180 days, and

(b) a second step for prophylactic treatment after clinical remission ofsymptoms comprising once daily administration of about 800 mg ofsulfamethoxazole, about 160 mg of trimethoprim, and at least about 20billion cells of probiotics, for a period from 120 to 180 days.

While ulcerative colitis rarely remits completely, the risk of relapsecan be greatly reduced with continued proactive treatment according tothe invention, and thus the protocols of the invention provide a newdirection for the treatment of inflammatory bowel disease. The inventionmay achieve and maintain remission without incurring the significanttoxic side-effects related to steroids and immunosuppressants, and formany patients suffering from chronic inflammation, the invention maymitigate the prospect for colorectal surgery.

These and other aspects of the invention will be better understood byreading of the following detailed description and appended claims.

DETAILED DESCRIPTION

The role of pharmabiotics in the treatment of IBD is well-documented.The present invention envisions the treatment or prophylaxis ofinflammatory bowel disease, including ulcerative colitis (UC) andCrohn's disease (CD), using antibiotics in combination with probiotics.The invention is based on early intervention with targeted antibioticsthrough control of dosage and duration of treatment, to eradicateinvasive or commensal bacterial infection which may allow forrestoration of the gut epithelial barrier, with the help of selectiveprobiotics. It is postulated that the immune response may “reset” oncethe offending antigen is completely eradicated and the immune system isunburdened by toxic immunosuppressants, thus leading to an improvedprognosis.

The method of the invention entails treatment of individuals sufferingfrom UC, CD, or any other form of IBD. The UC or CD may be in the activestage or in remission during treatment. In one embodiment, the treatmentis targeted to a patient for whom a clinical diagnosis of IBD, and inparticular UC or CD, has been made. The patient may be a male, female,adult, geriatric or pediatric patient. Veterinary use, particularly formammals, is also contemplated.

The invention provides a treatment regimen which involves dailyadministration of antibiotics and probiotics to a patient in needthereof. The administration is preferably oral, but other routes arealso contemplated, including for example, rectal administration. Wherethe patient is in the active stage of disease, the treatment is carriedout daily for a period of time sufficient to resolve one or more of thesymptoms of IBD, which typically will be at least 120 days, preferablyat least 150 days, and more preferred still at least 180 days. Once theIBD symptoms abate, the treatment is preferably carried out for anadditional period of time to kill any remaining latent spores in theintestines. This additional treatment will typically comprise dailyadministration, albeit with a fraction of the initial dose, for example,half of the therapeutic dose used in the initial treatment regimen, andtypically will be for at least 120 days, preferably at least 150 days,and more preferred still at least 180 days. The goal of the follow-ontreatment is to reduce the risk of relapse.

In the initial treatment stage, when the disease is active, it ispreferred to give an oral dose twice daily (B.I.D.). However, oncedaily, as well as more frequent administration, is contemplated. Thedosages can be taken, for example, in the morning and before bed, andcan be taken with or without a meal. In the maintenance stage, i.e.,after a flare-up has resolved, once daily dosing is contemplated,although more or less frequent administration is likewise within thescope of the invention.

The treatment regimen comprises administration, preferably oraladministration, of an antibiotic drug and a probiotic formulation, inamounts effective to reduce colonization of invasive bacteria, such asadherent-invasive Escherichia coli (AIEC) and/or enteroinvasiveEscherichia coli (EIEC), Salmonella, and various strains of Shigella inthe gastrointestinal tract. Without wishing to be bound to anyparticular theory, it is believe that bacterial infection may be atrigger cause of inflammation in IBD. This theory finds support in theobservation that biopsies of inflamed tissue show high levels ofinvasive strains of E. Coli and the number of bacteria in the inflamedregion correlates with the severity of bowel inflammation, as well asthe fact that animals raised in germ-free environments do not developcolitis. Also, the linkage of Mycobacterium paratuberculosis to UC andCD is highly suggestive in T-cell activation, implicating this bacteriumin the etiology of IBD.

This invention counteracts the action of antibiotics in destroyinghealthy colonies of microflora in the gut and mitigates the risk ofdeveloping opportunistic infection by competing bacteria in theintestine, including Clostridium difficile. Consequently, it is believedthat the inventive combination permits a higher dose of antibiotic to beemployed for a longer duration than would be possible in the absence ofthe probiotic mixture. In this manner, not only is it possible toresolve symptoms of IBD, but the treatment allows for the eradication oflatent spores, thereby reducing the probability of relapse.

In the broadest sense of the invention, any antibiotic drug havingactivity against invasive bacterial infections of the intestines iscontemplated to be useful. The antibiotic component may havebactericidal and/or bacteriostatic activity against the invasivespecies. Preferred antibiotics will have an activity against at leastone bacteria selected from the group consisting of Escherichia coli (E.coli), enterotoxigenic strains of E. coli (ETEC) that cause bacterialgastroenteritis, indole-positive Proteus species, Proteus mirabilis,Proteus vulgaris, Morganella morganii, Klebsiella species, Enterobacterspecies, Haemophilus influenzae, Streptococcus pneumoniae, Shigellaflexneri, or Shigella sonnei. However, antibiotics having activityagainst E. Coli, and in particular invasive strains of E. Coli arefavored. Preferably, the antibiotic component is active againstenterotoxigenic strains of E. coli, adherent-invasive E. coli (AIEC)and/or enteroinvasive E. coli (EIEC) in the gastrointestinal tract.

The mechanism of action of the antibiotic drug is not important,provided that it is effective in reducing infection of invasive speciesin the intestines. However, in one embodiment, it has been found usefulto employ an antibiotic that inhibits folate synthesis in bacteria. Thispathway involves a multi-step synthesis for the production oftetrahydrofolic acid, an essential coenzyme in many biologic reactions,particularly those relating to the synthesis of amino acids and nucleicacids. Useful antibiotic may act on any stage in the bacterial folatesynthesis pathway, and may inhibit the bacterial synthesis of one ormore intermediates of the tetrahydrofolic synthesis pathway, such asdihydrofolic acid.

In one embodiment, the antibiotic component comprises a drug whichinhibits a first step of the tetrahydrofolic synthesis pathway involvingthe synthesis of dihydropteroic acid from dihydropteroate diphosphateand para-aminobenzoic acid (PABA), catalyzed by the enzymedihydropteroate synthetase. Specifically, the antibiotic drug may act asa false-substrate inhibitor of dihydropteroate synthetase and competewith PABA for binding to dihydropteroate synthetase. Suitableantibiotics therefore include drugs that are competitive inhibitors ofbacterial dihydropteroate synthetase, including para-aminobenzoic acid(PABA) analogs.

On such class of drugs are the antibacterial sulfonamides, namely4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide, which has thegeneric name sulfamethoxazole. Sulfamethoxazole has the molecularformula of C₁₀H₁₁N₃O₃S, and the following structure:

The antibiotic component may also comprise a drug that inhibits the laststep in the tetrahydrofolic acid synthesis pathway in bacteria, whichinvolves the conversion of dihydrofolic acid to tetrahydrofolic acidwith the enzyme dihydrofolate reductase. In particular, the antibioticdrug may inhibit the synthesis of tetrahydrofolic acid by, for example,inhibiting the activity of dihydrofolate reductase. A suitable compoundfor inhibiting dihydrofolate reductase is5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine, which has thegeneric name trimethoprim, the molecular formula of C₁₄H₁₈N₄O₃, and thestructure:

In a preferred embodiment, the antibiotic component may comprise atleast two drugs that affect distinct steps in the bacterial biosynthesisof tetrahydrofolate. Preferred is a combination of a drug thatcompetitively inhibits the activity dihydropteroate synthetase with adrug that inhibits dihydrofolate reductase in bacteria. In particular,the antibiotic component may include a combination of trimethoprim andsulfamethoxazole.

In certain embodiments, the antibiotic component may comprise acombination of trimethoprim and sulfamethoxazole in a weight ratio fromabout 1:2 to about 1:50, preferably from about 1:3 to about 1:30, morepreferably from about 1:4 to about 1:25, even more preferred still fromabout 1:5 to about 1:20. In a specific embodiment, the antibioticcomponent may comprise a combination of trimethoprim andsulfamethoxazole in a ratio of 1:5.

In some embodiments, the antibiotic component may comprise from about 40mg to about 320 mg of trimethoprim, more typically from about 80 mg toabout 160 mg of trimethoprim. In certain embodiments, the antibioticcomponent may comprise about 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg,100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or about 160 mg oftrimethoprim. In some embodiments, the antibiotic component may comprisefrom about 200 mg to about 1,600 mg of sulfamethoxazole, more typicallyfrom about 400 mg to about 800 mg of sulfamethoxazole. In certainembodiments, the antibiotic component may comprise about 200 mg, 250 mg,300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg,750 mg, or about 800 mug of sulfamethoxazole. In one embodiment, theantibiotic component comprises 80 mg of trimethoprim in combination with400 mg of sulfamethoxazole. In another embodiment, the antibioticcomponent comprises 160 mg of trimethoprim in combination with 800 mg ofsulfamethoxazole.

Other antibiotic drugs which may be used include, without limitation,vancomycin; amoxicillin; tetracyclines; clarithromycin; clindamycin; amember of the cephlosporin antibiotic family (e.g., cefaclor,cefadroxil, cefixime, cefprozil, ceftriaxone, cefuroxime, cephalexin,loracarbef, and the like); a member of the penicillin family ofantibiotics (e.g., ampicillin, amoxicillin/clavulanate, bacampicillin,cloxicillin, penicillin VK, and the like); a member of thefluoroquinolone family of antibiotics (e.g., ciprofloxacin,grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin,sparfloxacin, trovafloxacin, and the like); or a member of the macrolideantibiotic family (e.g. azithromycin, crythromycin, and the like).Specific mention may be made of the following preferred antibiotics, andin particular at the dosages indicated: levofloxacin (e.g., 250 mg, 500mg, or 750 mg), metronidazole (e.g., 250 mg, 500 mg, or 750 mg),ciprofloxacin (e.g., 100 mg, 250 mg, 500 mg, or 750 mg), amoxicillin(e.g., 125 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 775 mg, or 875mg), erythromycin (e.g., 250 mg, 333 mg, or 500 mg), vancomycin (e.g.,125 mg or 250 mg), and clindamycin (e.g., 75 mg, 150 mg, or 300 mg),each of which may be used alone or in combination with otherantibiotics. Each of the forgoing dosages may be administered up to themaximum safe daily dosage for each given drug. The may constitute, forexample, administration of one, two, three, four, or more of theforegoing doses daily. In one embodiment, the treatment comprises oraladministration of trimethoprim and sulfamethoxazole, optionally incombination with at least one other antibiotic drug selected from thegroup consisting of levofloxacin, metronidazole, ciprofloxacin,amoxicillin, crythromycin, vancomycin, clindamycin, and combinationsthereof.

The second component of the compositions and treatment methods accordingto the invention is a probiotic formulation. The digestive systems ofhumans and other mammals include bacteria essential to the health of thegastrointestinal system and overall heath of the individual. Beneficialtypes of bacteria, such as lactic acid bacteria, provide various healthbenefits, including enhancing digestion, nutrient absorption, bowelfunction, and natural immunity. Also, beneficial bacteria may producevitamins and, moreover, may inhibit the growth of pathogenicmicroorganisms, such as pathogenic bacteria, viruses, and/or protozoa.Beneficial bacteria may inhibit the growth of such undesirablemicroorganisms, for example, by secreting bacteriocins and/or substancesthat reduce gastrointestinal tract pH, thereby making thegastrointestinal environment less hospitable to pathogenicmicroorganisms. Disruption of the balance of the normal intestinal floracan lead to conditions ranging from mild gastrointestinal symptoms toserious infection.

Examples of probiotics useful in the present invention include, withoutlimitation, bacteria selected from the group consisting ofBifilobacterium, Lactobacillus, Streptococcus, Propionibacterium, andEnterococcus, and mixture thereof. Particular non-limiting examples ofprobiotics include Arthrobacter agilis, Arthrobacter citreus,Arthrobacter globiformis, Arthrobacter leuteus, Arthrobacter simplex,Azotobacter chroococcum, Azotobacter paspali, Azospirillumbrasiliencise, Azospriliium lipoferum, Bacillus brevis, Bacillusmacerans, Bacillus pumilus, Bacillus polymyxa, Bacillus subtilis,Bacteroides lipolyticum, Bacteroides succinogenes, Brevibacteriumlipolyticum, Brevibacterium stationis, Bacillus laterosporus, Bacillusbifidum, Bacillus laterosporus, Bifidophilus infantis, Streptococcusthermophilous, Bifodophilus longum, Bifidobacteria animalis,Bifidobacteria bifidus, Bifidobacteria breve, Bifidobacteria longum,Kurtha zopfil, Lactobacillus paracasein, Lactobacillus acidophilus,Lactobacillus planetarium, Lactobacillus salivarius, Lactobacillusrueteri, Lactobacillus bulgaricus, Lactobacillus helveticus,Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus sporogenes,Lactococcus lactis, Myrothecium verrucaris, Pseudomonas calcis,Pseudomonas dentrificans, Pseudomonas flourescens, Pseudomonas glathei,Phanerochaete chrysosporium, Saccharomyces boulardii, Streptmycesfradiae, Streptomyces cellulosae, Streptomyces griseoflavus, andcombinations thereof.

Special mention may be made of lactic acid bacteria (LAB) andbifidobacteria. In some embodiments, the probiotic component comprisescells or spores of at least one strain selected from the groupconsisting of Bifidobacterium bifidum, Bifidobacterium breve,Bifidobacterium longum, Saccharomyces boulardii, Lactobacillusacidophilus, Lactobacillus bulgaricus, Lactobacillus paracasein, andcombinations thereof. Commercially available probiotic formulationsinclude Culturelle® from Amerifit Brands, Inc., which containsLactobacillus GG, and VSL#3® from VSL Pharmaceuticals, Inc. whichcontains Lactobacillus and Bifidobacterium and is positioned for thetreatment of IBD.

In one embodiment, the probiotic mixture comprises Bifidobacteriumbifidum. In one embodiment, the probiotic mixture comprisesBifidobacterium breve. In one embodiment, the probiotic mixturecomprises Bifidobacterium longum. In one embodiment, the probioticmixture comprises Saccharomyces boulardii. In one embodiment, theprobiotic mixture comprises Lactobacillus acidophilus. In oneembodiment, the probiotic mixture comprises Lactobacillus bulgaricus. Inone embodiment, the probiotic mixture comprises Lactobacillusparacasein.

In some embodiments, the dose is from about 1×10³ to about 1×10¹² colonyforming units (cfu) of probiotic, from about 1×10⁵ to about 1×10¹² cfuof probiotic, or from about 1×10⁷ to about 1×10¹² cfu of probiotic, perday. The probiotic mixture will typically comprise at least 500 millioncells or spores, more typically at least 1 billion, preferably at least5 billion, more preferably at least 10 billion, and more preferred stillat least 20 billion cells or spores. During the treatment regimen, wherethe dosing is twice daily, up to 40 billion cells or spores or even morewill be ingested daily.

In certain embodiments, a purified, isolated, and/or genetically alteredbacterial strain can be used. For example, a strain can be geneticallyaltered in a number of different ways to increase efficacy. Exemplarymethods are described in Methods in Cloning Vol. 3, eds. Sambrook andRussell, Cold Spring Harbor Laboratory Press (2001) and references citedtherein. In addition, probiotic bacteria of the present invention can beobtained commercially. A variety of beneficial bacteria are commerciallyavailable from American Type Culture Collection Catalogue (Rockville,Md.). Beneficial bacteria can also be obtained by culturing, forexample, in liquid, or on solid media, following routine and establishedprotocols, and isolated from the medium by conventional means. Exemplarymethods are described in Methods in Cloning Vol. 3, eds. Sambrook andRussell, Cold Spring Harbor Laboratory Press (2001) and references citedtherein.

Additional examples of probiotics include strains of Bifidobacteriumisolated from the human gastrointestinal tract, e.g., see WO 00/42168;strains of Bifidobacterium infantis disclosed in U.S. Pat. No.7,195,906; and other bacterial and microbe strains disclosed in U.S.Patent Pub. No. 2008/0241226, the contents of each of which are hereinincorporated by reference in their entireties.

In some embodiments, the probiotic is dried. Drying may comprise spraydrying, fluid bed drying, or freeze-drying. In some embodiments, forexample, a cell suspension is treated with proteins, maltodextrins,trehalose, and optionally, other stabilizing or freeze-protecting agentslike ascorbic acid, to form a viscous paste, which is submitted tofreeze-drying. The so-obtained material can be grinded to appropriatesize in suitable dosage forms.

What is important is that the probiotic formulation provide a sufficientnumber of cells to substantially maintain levels of microflora in thegastrointestinal tract during the course of treatment. The levels ofmicroflora in the gastrointestinal tract at the end of the treatmentregimen may be, for example, greater than the levels that wouldotherwise be present at the end of the course of treatment were theprobiotic mixture not administered. The methods are also useful forreducing the risk of C. difficile infection during antibiotic treatmentof IBD.

The use of probiotics may have ancillary benefits including treatment ofabdominal cramps, abdominal discomfort, abdominal distension, antibioticassociated diarrhea (AAD), belching, bloating, celiac disease,cholecystitis, Clostridium difficile associated diarrhea (CDAD), Crohn'sdisease, constipation (including chronic or functional constipation),diarrhea (including chronic or functional diarrhea), disorders ofmotility, diverticulitis or diverticular disease, duodenal ulcers,dyspepsia (including functional dyspepsia), erosive esophagitis, excessflatus, gall bladder disease, gastroesophageal reflux disease (GERD),gastroparesis, gastritis, gastric ulcers, halitosis, heartburn,hypersecretory conditions such as Zollinger-Ellison syndrome,inflammatory bowel disease (IBD), irritable bowel syndrome (IBS),lactose intolerance, motion sickness, multiple endocrine adenomas,nausea, pain, posterior laryngitis, post-infection colitis, pouchitis,small intestine bacterial overgrowth (SIBO) or small bowel bacterialovergrowth (SBBO), spasm, spastic colon, stomach problems, systemicmastocytosis, ulcerative colitis (UC), visceral hypersensitivity,vomiting, and the like.

The treatment methods are contemplated to be useful for the treatment,prevention, amelioration, or reduction of symptoms of inflammatory boweldisease. Also provided, are methods for the treatment or prophylaxis ofulcerative colitis (UC) and/or Crohn's disease (CD). The method willfind utility in the treatment of UC in either the active stage or duringremission to prevent or reduce the probability or occurrence of relapse.

In severe cases of IBD, conventional treatment relies on suppression ormodulation of the immune system. Immunosuppressants includingazathioprine, methotrexate, and 6-mercaptopurine have been suggested inthe treatment of IBD. However, the use of immunosuppressants iscontroversial because they do not address the underlying cause ofillness and their severe side-effects may outweigh their benefits.Indeed, it has been suggested by researchers at University CollegeLondon, who question the wisdom of suppressing the immune system in CDand UC patients, that the problem may be an underactive, rather than anoveractive immune system. Therefore, in the preferred practice of thepresent invention, the patient is not administered an immunosuppressantor immunomodulatory drug during the treatment regimen, or if the patienthad been on immunosuppressant or immunomodulatory drugs prior tostarting the treatment, the levels of immunosuppressant orimmunomodulatory drugs are preferably reduced or substantiallyeliminated during treatment. In some embodiments, the patient is notadministered azathioprine, methotrexate, or 6-mercaptopurine during thetreatment regimen or the levels of these drugs are reduced. In anotherembodiment, the patient is not administered a TNF-α inhibitor during thetreatment regimen. The diminished use of immunosuppressants may resultin unhindered DNA/RNA repair mechanisms.

While not strictly necessary, it may be beneficial to include dailyadministration of an aminosalicylate, such as mesalamine(5-aminosalicylic acid), in conjunction with the treatment protocol.Mesalamine is marketed in the United States under the names Asacol andLialda. Mesalamine is preferably administered in an mount from about 3.6g to about 4.8 g daily. In one embodiment, 9-12 tablets of 400 mg ofAsacol (mesalamine) are given daily. In another embodiment, 3-4 tabletsof 1.2 g of Lialda (mesalamine) are given daily. However, in someembodiment, the patient is not treated with aminosalicylates.

It has also been found useful to administer fish oil or other sources ofomega-3 fatty acids including eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA). In one embodiment, at least 1,000 mg ofomega-3 fatty acids daily are taken daily, and more preferably twicedaily. Other dietary measures are recommended in concert with thetreatment regimen, including for example, limiting alcohol and refinedsugars, limiting or eliminating gluten, wheat, whey, red meat and dairyproducts, and limiting fat intake. It also may be desirable to limit oreliminate folic acid and/or iron supplements.

Once the primary symptoms of IBD have subsided, the dosage of antibioticcan be reduced, and may be cut in half. It is important to continue thetherapy, however, to eradicate any latent spores of invasive bacteria.Failure to totally eradicate the offending bacterial pathogen along withlingering spores may contribute to perpetuating a state of chronicinflammation and, consequently, lessen the possibility of remission.Once full clinical remission is noted, the treatment regimen is stopped,but it may be desirable to continue to administer probiotics daily inorder to maintain the microflora in the gut and inhibit colonization ofinvasive species.

Preferred methods for the treatment or prophylaxis of inflammatory boweldisease comprise daily oral administration to a patient in need thereoffor a period of at least 120 days (preferably for 180 days) a dose ofabout 1,600 mg daily of sulfamethoxazole, 320 mg daily of trimethoprim,and a probiotic mixture comprising at least about 40 billion cells. Theprobiotic will preferably comprise at least one strain selected from thegroup consisting of Bifidobacterium bifidum, Bifidobacterium breve,Bifidobacterium Infantis, Bifidobacterium longum, Saccharomycesboulardii, Lactobacillus acidophilus, Lactobacillus bulgaricus,Lactobacillus paracasein, and combinations thereof.

In one variant, the patient is administered 800 mg of sulfamethoxazoletwice daily and 160 mg of trimethoprim twice daily for a time sufficientto affect remission of one or more symptoms of inflammatory boweldisease, after which the patient is administered 800 mg ofsulfamethoxazole once daily and 160 mg of trimethoprim once daily for aperiod of at least 90-120 days after the onset of remission. The dosingalso may be based on the patient's weight. For example, adult patientsweighing up to 175 pounds, or up to 190 pounds, may be administered twotablets daily, whereas patients over 190 pounds may be administered 2½tablets daily, each tablet comprising 800 mg of sulfamethoxazole and 160mg of trimethoprim.

This invention has the potential to prevent pathogenic microorganismsfrom upsetting the balance of normal gut flora and destabilizing thegastrointestinal tract, while eradicating the invasive pathogen. Theresults of treatment may include (1) disruption of the cycle of chronicinflammation allowing for restoration of the gut epithelial barrier; (2)preventing or minimizing translocation of intestinal bacterial to otherorgans; (3) reversing or preventing side effects of antibiotic therapy;(4) minimizing a causal effect leading to C. Difficile via antibiotics;(5) eradicating pathogenic bacteria strains along with its components;(6) produce quality, long-term remission, (7) recolonize and maintainthe balance of intestinal flora; (8) disrupt the chain of events leadingto the immune/inflammatory response, cellular changes, and chronicinflammation; (9) allow for increased absorption; (10) modulatetranscription of Tumor Necorsis Factor-A (TNF-a); (11) possibly mitigatethe risk of colorectal cancer due to chronic inflammation; and (12)achieve and maintain remission without incurring the significant toxicside effects related to steroids and immunosuppressants.

In one embodiment, the sulfamethoxazole, trimethoprim, and probioticmixture are present in a single dosage form, although it is alsopossible that the sulfamethoxazole and said trimethoprim are included ina first dosage form and the probiotic mixture is present in a seconddosage form. When the antibiotics and the probiotics are included inseparate dosage forms, it is preferred, but not strictly necessary, thatthey be administered substantially simultaneously.

The oral dosage form will typically comprise at least about 1 billioncells of probiotics, at least about 2 billion cells of probiotics, atleast about 5 billion cells of probiotics, at least about 10 billioncells of probiotics, or at least about 20 billion cells of probiotics,based on the collective number of cells of all species and strains.

In embodiments in which the dosage form comprises about 800 mg ofsulfamethoxazole and about 160 mg of trimethoprim, at least about 20billion cells of probiotic will be included. For example, the dosageform may comprise:

about 5 billion cells of Bifidobacterium bifidum;

about 2 billion cells of Bifidobacterium breve;

about 2 billion cells of Bifidobacterium infantis;

about 2 billion cells of Bifidobacterium longum;

about 5 billion cells of Lactobacillus acidophilus;

about 500 million cells of Lactobacillus bulgaricus;

about 2 billion cells of Lactobacillus paracasein; and

about 2.5 billion cells of Saccharomyces boulardii.

In embodiments in which the dosage form comprises about 400 mg ofsulfamethoxazole and about 80 mg of trimethoprim, at least about 10billion cells of probiotic will be included. In this “half-strength”formulation, the dosage form may include half the amount of cells listedabove for each species. In embodiments in which the dosage formcomprises about 200 mg of sulfamethoxazole and about 40 mg oftrimethoprim, at least about 5 billion cells of probiotic will beincluded, in which case the dosage form may include one quarter of theamount of cells listed above for each species.

Those of skill in the art will appreciate that microorganisms that areintended to act in the intestinal tract should be protected against theacidic gastric juice of the stomach. Preferred dosage forms include anenteric tablet, capsule, powder or granulate that will survive thestomach and arrive intact in the intestine. Further, embeddedmicroorganisms in a carrier or protective matrix may tend to cake due tohygroscopicity, impeding flowability and reducing storage stability.Techniques for achieving low hygroscopicity and good flowability intablets, capsules, and the like, and especially in powdered productsinvolving microorganisms, are described, e.g., in U.S. Patent Pub. No.2009/0214647, which is incorporated herein by reference in its entirety.

The oral dosage form may comprise tablets, capsules, powders or sachets,but will typically be in the form a tablet. The tablet can be amodified-release tablet, including sustained release and delayedrelease. The dosage form can be designed according to any of themodified release dosage forms known in the art and described, forexample, in U.S. Pat. No. 7,108,865, the disclosure of which is herebyincorporated by reference, and using any of the carriers, coatings,excipients, and tablet designs in the patent.

In some embodiments, the antibiotic and probiotic components arecompressed with a binder together into a solid core. In one embodiment,the probiotic component is in a solid core and the antibiotic iscontained in a layer surrounding the core. In another embodiment, theantibiotic component is in a solid core and the probiotic is containedin a layer surrounding the core. In each case, the tablet may furthercomprise a water-soluble, water-insoluble, or enteric coatingsurrounding the outer layer.

Enteric and other pH-sensitive polymers which are relatively insolubleand impermeable at the pH of the stomach, but which are more soluble andpermeable at the pH of the small intestine and colon includepolyacrylamides, phthalate derivatives such as acid phthalates ofcarbohydrates, amylose acetate phthalate, cellulose acetate phthalate,other cellulose ester phthalates, cellulose ether phthalates,hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate,hydroxypropylmethylcellulose phthalate, methylcellulose phthalate,polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate,sodium cellulose acetate phthalate, starch acid phthalate,styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acidpolyvinylacetate phthalate copolymer, styrene and maleic acidcopolymers, polyacrylic acid derivatives such as acrylic acid andacrylic ester copolymers, polymethacrylic acid and esters thereof, polyacrylic methacrylic acid copolymers, shellac, and vinyl acetate andcrotonic acid copolymers. Preferred pH-sensitive polymers includeshellac; phthalate derivatives, particularly cellulose acetatephthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulosephthalate; polyacrylic acid derivatives, particularly polymethylmethacrylate blended with acrylic acid and acrylic ester copolymers; andvinyl acetate and crotonic acid copolymers.

In some embodiments, the antibiotic drug and the probiotic mixture arecontained together within a core surrounded by an enteric coating or adelayed release coating. A delayed release coating can be, for example,a coating of a water-insoluble polymer such as ethylcellulose which maybe impregnated with water-soluble materials that dissolve in the stomachand create pores in the coating.

In another embodiment, only the probiotic component is encapsulated inan enteric coating which releases the probiotic mixture in the smallintestine. These microcapsules of encapsulated probiotic may be combinedin a dosage form with the antibiotic which may or may not beencapsulated in an enteric coating or modified release coating material.The antibiotic also may, for example, be provided in the form ofmicrocapsules or the like, with or without a modified-release coating.The microcapsules of probiotic and the microcapsules of antibiotic maybe charged into a capsules or may be tableted together. Such an oraldosage form provides release of the antibiotic drug at a first locationand/or time in the gastrointestinal tract and release of the probioticmixture at a second location and/or time in the gastrointestinal tract.This can also be accomplished by selection of the appropriate dosageform, including the use of tablets having multiple layers, including forexample, a core comprising the probiotic material, a coating surroundingthe core comprising an enteric or delayed release coating, and anexternal layer comprising the antibiotic for immediate release.Alternatively, the tablet may be an osmotic device comprising awater-insoluble shell having a passage therethrough to permit water fromthe gut to penetrate the shell and dissolve the carrier contained withinthe shell, thereby releasing the drug or probiotic contained within theshell. The core may comprise a first carrier, proximal to the passagewhich releases the antibiotic first, and a second carrier distal to thepassage which releases the probiotic only after the antibiotic has beensubstantially released.

The antibiotic and probiotic may be dispersed in any pharmaceuticallyacceptable carrier, which may be an immediate release or a slow releasecarrier. The carrier may comprise micro-crystalline cellulose (MCC),dextran, corn starch, flour, talc, sucrose, mannitol, lactose, calciumcarbonate, polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinyl alcohol(PVA) or the like. The carrier will typically be compressed into a coreand then coated with a polymeric coating to modify the release profileof the contents. The coating may comprise a water-soluble polymer suchas polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone),or polyethylene glycol, or a water insoluble polymer selected from thegroup consisting of ethers of cellulose, esters of cellulose, celluloseacetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based onethylacrylate and methylmethacrylate, copolymers of acrylic andmethacrylic acid esters with quaternary ammonium groups, pH-insensitiveammonio methacrylic acid copolymers, and mixtures thereof. The coatingmay comprise a natural polymer such as methylcellulose, ethylcellulose,hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC),hydroxypropyl cellulose (HPC), or a combination therefore. The use ofmethylcellulose in combination with hydroxypropyl methyl cellulose(HPMC) is well known.

Standard ingredients and methods of preparation of tablets, includingmodified release tablets are described in “Remington: The science andpractice of pharmacy,” (1995), herein incorporated by reference.Additional excipients include, without limitation, lubricants,disintegrants, and the like. The tablets may be scored to permit them tobe easily broken into two substantially equal portions to facilitateswallowing.

EXAMPLES Example 1

A male patient with a clinical diagnosis of chronic ulcerative colitisregularly suffered relapses following a variety of treatments, includingAsacol, Purinethol, Colazal, Rifaximin, Remicade, Flagyl, Clindamycin,Cyclosporine, Cipro, Cortifoam, and Budesonide. The chronic conditionpersisted for about 35 years, failed to go into prolonged remission, andwas characterized by frequent relapse. The patient failed all previousprotocols and was facing surgical intervention. The patient wasadministered Septra DS tablets (160 mg trimethoprim and 800 mgsulfamethoxazole) twice daily for 360 days to treat an unrelatedvasculitis. Concurrently, the patient orally ingested probiotic capsules(40 billion cells daily), along with Omega-3 fish oil capsules (1,000 mgdaily), 50 mg of 6-mercaptopurine daily, and 12 tablets daily of 400 mgAsacol. After 90 days, the colitis symptoms were improved and after 180days, the patient was in clinical remission. After 180 days, tablets oftrimethoprim (160 mg) and sulfamethoxazole (800 mg) were administeredonce daily for an additional 180 days with continued use of probiotics,6-mercaptopurine, and Omega-3 fish oil. The patient has beenasymptomatic for over three years.

Example 2

Representative tablets according to the invention have the formulationprovided in Table 1. These are multi-layer tablets having animmediate-release layer of probiotics around a delayed-release layer ofantibiotic. The delayed-release layer of antibiotic is encapsulated inan enteric coating which dissolves at a pH of 7 or greater to ensurethat the antibiotic is substantially released in the small intestine,and in particular in the terminal ileum, rather than in the stomach. Thetablets may be full-strength, in which case the treatment protocolrecommends twice daily administration, or the tablets may behalf-strength, in which case four tablets daily are required during thetreatment regimen.

TABLE 1 Composition of tablets. full-strength half-strengthDelayed-release antibiotic layer sulfamethoxazole 800 mg 400 mgtrimethoprim 160 mg 80 mg Immediate-release probiotic layerBifidobacterium bifidum ~5 billion cells ~2.5 billion cellsBifidobacterium breve ~2 billion cells ~1 billion cells Bifidobacteriuminfantis ~2 billion cells ~1 billion cells Bifidobacterium longum ~2billion cells ~1 billion cells Lactobacillus acidophilus ~5 billioncells ~2.5 billion cells Lactobacillus bulgaricus ~500 million cells~250 million cells Lactobacillus paracasein ~2 billion cells ~1 billioncells Saccharomyces boulardii ~2.5 billion cells ~1.75 billion cells

A treatment protocol according to the invention includes a firsttreatment step during the active phase of disease and, after clinicalremission, a prophylaxis step to reduce the likelihood of recurrence ofsymptoms. A representative treatment regimen is as follows:

Treatment: 1 full-strength tablet, every 12 hours for 180 days.

Maintenance and Prophylaxis: 1 full-strength tablet, daily for 90 days.

Of course, it will be recognized that the treatment regimen may bemodified if the half-strength tablets are used by administering two ofsuch tablets in place of each full-strength tablet. The treatmentregimen also allows for decreased levels of immunosuppressants(antimetabolites) and, if it is feasible to do so without adversereactions, the total elimination of immunosuppressants. Ananti-inflammatory such as mesalamine (Asacol or Lialda) may also be usedin conjunctions with the antibiotic/probiotic therapy. For example, six400 mg Asacol tablets may be administered twice daily for the durationof the treatment regimen. The treatment may further include thefollowing dietary adjustments:

Fish oil capsules, Omega-3, 1000 mg, 1 tablet 2× daily for 180 days.

Limit alcohol and refined sugar intake for 90 days.

Eliminate gluten, wheat, whey, red meat and dairy for 90 days.

Limit fat intake for 90 days.

Reduce or eliminate folic acid and/or iron supplements.

All patents and patent publications referred to herein are herebyincorporated by reference. Certain modifications and improvements willoccur to those skilled in the art upon a reading of the foregoingdescription. It should be understood that all such modifications andimprovements have been deleted herein for the sake of conciseness andreadability but are properly within the scope of the following claims.

I claim:
 1. An oral dosage form for the treatment or prophylaxis ofinflammatory bowel disease due to bacterial infection, said dosage formcomprising: (i) a delayed-release component comprising an amount ofantibiotic effective to reduce colonization of pathogenic bacteria inthe gastrointestinal tract, said antibiotic comprising a combination ofsulfamethoxazole and trimethoprim; and (ii) an immediate-releasecomponent comprising a probiotic formulation in an amount effective torestore normal microflora colonies in the gut; wherein saidimmediate-release component releases said probiotic formulation uponcontact with fluid in the stomach; and wherein said delayed-releasecomponent releases said antibiotic at a pH of 7 or greater.
 2. The oraldosage form according to claim 1, wherein said probiotic formulationcomprises at least one strain selected from the group consisting ofBifidobacterium bifidum; Bifidobacterium breve; Bifidobacteriuminfantis; Bifidobacterium longum; Lactobacillus acidophilus;Lactobacillus bulgaricus; Lactobacillus paracasein; Saccharomycesboulardii, and combinations thereof.
 3. The oral dosage form accordingto claim 1, wherein said antibiotic comprises from about 200 mg to about800 mg of sulfamethoxazole and from about 40 mg to about 160 mg oftrimethoprim.
 4. The oral dosage form according to claim 2, wherein saidantibiotic comprises about 800 mg of sulfamethoxazole and about 160 mgof trimethoprim and wherein said probiotic formulation comprises atleast about 10 billion cells.
 5. The oral dosage form according to claim3, wherein said probiotic formulation comprises: about 5 billion cellsof Bifidobacterium bifidum; about 2 billion cells of Bifidobacteriumbreve; about 2 billion cells of Bifidobacterium infantis; about 2billion cells of Bifidobacterium longum; about 5 billion cells ofLactobacillus acidophilus; about 500 million cells of Lactobacillusbulgaricus; about 2 billion cells of Lactobacillus paracasein; and about2.5 billion cells of Saccharomyces boulardii.
 6. The oral dosage formaccording to claim 2, wherein said antibiotic comprises about 400 mg ofsulfamethoxazole and about 80 mg of trimethoprim and wherein saidprobiotic formulation comprises at least about 5 billion cells.
 7. Theoral dosage form according to claim 3, wherein said probioticformulation comprises: about 2.5 billion cells of Bifidobacteriumbifidum; about 1 billion cells of Bifidobacterium breve; about 1 billioncells of Bifidobacterium infantis; about 1 billion cells ofBifidobacterium longum; about 2.5 billion cells of Lactobacillusacidophilus; about 250 million cells of Lactobacillus bulgaricus; about1 billion cells of Lactobacillus paracasein; and about 1.75 billioncells of Saccharomyces boulardii.
 8. A method for the treatment orprophylaxis of inflammatory bowel disease due to bacterial infectioncomprising administering to a patient in need thereof, an oral dosageform comprising: (i) a delayed-release component comprising an amount ofantibiotic effective to reduce colonization of pathogenic bacteria inthe gastrointestinal tract, said antibiotic comprising: from about 200mg to about 800 mg of sulfamethoxazole; and from about 40 mg to about160 mg of trimethoprim; and (ii) an immediate-release componentcomprising a probiotic formulation in an amount effective to restorenormal microflora colonies in the gut; wherein said immediate-releasecomponent releases said probiotic formulation upon contact with fluid inthe stomach; and wherein said delayed-release component releases saidantibiotic at a pH of 7 or greater.
 9. The method according to claim 8,wherein said delayed-release component releases said antibiotic in thesmall intestine.
 10. The method according to claim 9, wherein saiddelayed-release component releases said antibiotic primarily in theterminal ileum.
 11. The method according to claim 8, wherein saidprobiotic formulation comprises at least one strain selected from thegroup consisting of Bifidobacterium bifidum; Bifidobacterium breve;Bifidobacterium infantis; Bifidobacterium longum; Lactobacillusacidophilus; Lactobacillus bulgaricus; Lactobacillus paracasein;Saccharomyces boulardii, and combinations thereof.
 12. The methodaccording to claim 8, wherein said oral dosage form comprises about 400mg to about 800 mg of sulfamethoxazole and from about 80 mg to about 160mg of trimethoprim.
 13. The method according to claim 8, wherein saidoral dosage form comprises about 800 mg of sulfamethoxazole and about160 mg of trimethoprim and wherein said probiotic formulation comprisesat least about 10 billion cells.
 14. The method according to claim 8,wherein said oral dosage form comprises: about 5 billion cells ofBifidobacterium bifidum; about 2 billion cells of Bifidobacterium breve;about 2 billion cells of Bifidobacterium infantis; about 2 billion cellsof Bifidobacterium longum; about 5 billion cells of Lactobacillusacidophilus; about 500 million cells of Lactobacillus bulgaricus; about2 billion cells of Lactobacillus paracasei; and about 2.5 billion cellsof Saccharomyces boulardii.
 15. The method according to claim 8, whereinsaid oral dosage form comprises about 400 mg of sulfamethoxazole andabout 80 mg of trimethoprim and wherein said probiotic formulationcomprises at least about 5 billion cells.
 16. The method according toclaim 8, wherein said probiotic formulation comprises: about 2.5 billioncells of Bifidobacterium bifidum; about 1 billion cells ofBifidobacterium breve; about 1 billion cells of Bifidobacteriuminfantis; about 1 billion cells of Bifidobacterium longum; about 2.5billion cells of Lactobacillus acidophilus; about 250 million cells ofLactobacillus bulgaricus; about 1 billion cells of Lactobacillusparacasei; and about 1.75 billion cells of Saccharomyces boulardii. 17.The method according to claim 8, wherein said step of administeringcomprises either: (a) twice daily administration for a period from 120to 180 days for the treatment of active symptoms, or (b) once dailyadministration for a period from 120 to 180 days for prophylaxis afterclinical remission of symptoms.
 18. A method for the treatment orprophylaxis of inflammatory bowel disease due to bacterial infectioncomprising administering to a patient in need thereof, an oral dosageform comprising: (i) a delayed-release component comprising an amount ofantibiotic effective to reduce colonization of pathogenic bacteria inthe gastrointestinal tract, said antibiotic comprising: from about 200mg to about 800 mg of sulfamethoxazole; and from about 40 mg to about160 mg of trimethoprim; and (ii) an immediate-release componentcomprising a probiotic formulation in an amount effective to restorenormal microflora colonies in the gut; wherein said immediate-releasecomponent releases said probiotic formulation upon contact with fluid inthe stomach; and wherein said delayed-release component releases saidantibiotic in the small intestine.